IgE-mediated allergic disease appears to be very common particularly in industrialized countries where up to one quarter of the population is affected by allergic rhinitis. (Settipane, R. A., Allergy Asthma Proc, 22(4):185-9 (2001)). Furthermore people suffering from allergic rhinitis show a lower quality of life than healthy one, (Bousquet, J., et al., J Allergy Clin Immunol, 94(2):182-8 (1994)) with only a few going into remission spontaneously. Approximately 25% of all allergic patients respond to tree pollen. Among those, 90% show reactivity with birch pollen extract on cutaneous tests (Skin Prick Tests, SPT). Allergies are triggered by environmental proteins of known peptide sequence and for birch pollen allergy most patients show hypersensitivity to Bet v 1, the major birch pollen allergen. Bet v 1 is part of a protein family playing an important role in plant defense and thus Bet v 1 cross-reacting proteins were found in a number of plants. (Breiteneder, H. et al., J Allergy Clin Immunol, 113(5):821-30 (2004)). In addition, allergy to birch pollen is very often related to allergies to other trees of the Fagales family and with certain food allergies, like those to hazel nut, apple, melon and peach. (Son, D. Y. et al., Eur J Nutr, 38(4):201-15 (1999) and Jahn-Sclunid et al., J Allergy Clin Immunol, 116(1):213-9 (2005)).
The only treatment directed to the cause of IgE-mediated allergy is specific immunotherapy (SIT). The treatment consists in injecting increasing doses of allergens for extended periods of time (three to five years) to induce tolerance in the allergic patient. Several studies showed the benefit of this therapy on the allergic response, in particular upon long-term treatment. (Drachenberg, K. J. et al., Allergol Immunopathol, 31(2):77-82 (2003) and Dam Petersen, K. et al., Allergol Immunopathol 33(5)264-269 (2005)). However, a number of side effects were observed particularly during ultra rush therapies, where up to 30% of the patients have to be treated for allergic symptoms during the course of therapy. (Birnbaum et al., Clin. Exp. Allergy, 33(1):58-64 (2003)). There is thus a strong medical need for an alternative to SIT in the form of a shorter treatment with acceptable safety.
Different approaches have been tested to improve the safety and efficacy of SIT. Formulations or existing extracts have been improved by adding adjuvants, like MPL (Allergy Therapeutics), (Drachenberg, K. J. et al., Allergol Immunopathol, 31(5):270-7 (2003)) DNA sequences (Hartl, A. et al., Allergy, 59(1):65-73 (2004)) or bacteriophage combined with CpG (Martinez Gomez, J. M. et al., Pharm. Res., 24(10):1927-35 (2007)) which increase the TH1 immune response, thus allowing possible reductions in the amount of allergen extract. Defined allergens were used instead of whole extracts. In the case of birch pollen, a clinical trial with recombinant Bet v 1 has shown efficacy equivalent to whole birch pollen extract (Pauli, G. et al., J. Allergy Clin. Immunol, 122(5):951-60 (2008)).
To diminish the occurrence of allergic symptoms resulting from treatment, different groups explored the use of products with hypoallergenic potential, namely showing reduced IgE binding. In particular, peptides encompassing a restricted number of T-cell epitopes were used for allergen immunotherapy of cat dander with limited efficacy (Campbell, J D et al., J Exp Med., 206(7):1535-47 (2009)). However, allergens harbor a great variety of T cell epitopes partly dependent on the HLA type of the patient. For example, T cell epitopes were found scattered throughout the Bet v 1 sequence, except for a short region (Jahn-Schmid B. et al., J Allergy Clin Immunol, 116(1):213-9 (2005)). Thus an efficient immunotherapy product should preferably contain the complete sequence of the allergen rather than selected T-cell epitopes.
The use of fragments of allergens remains attractive, based on the evidence that human IgE recognize mainly non-contiguous epitopes which may be separated by fragmentation of the allergen. Two contiguous fragments of Bet v 1 or trimeric forms of Bet v 1 were tested in a phase I study in human and showed a trend towards improvement of well being but provided no significant improvement in symptom medication scores (Niederberger, V. et al., Proc Natl Acad Sci USA, 101(2):14677-82 (2004)). In that study, however, a number of adverse events were observed, the majority of which occurred hours after the injections (Purohit, A. et al, Clin Exp Allergy (2008)). Three fragments of the major allergen of bee venom, namely phospholipase A2, were also tested in human, showing an excellent safety due to lowered IgE binding while eliciting elevated levels of IgG4 and IL-10 (Fellrath et al., J. Allergy Clin. Immunol, 111:854-861 (2003)). A method was devised to select contiguous overlapping peptides (COPs) for treatment of allergy which together form the entire amino acid sequence of an allergen, thus providing all possible T cell epitopes of the allergen, while having lowered IgE binding (Patent application WO2004/081028 A2). Such selected fragments show a reduced ability to reform the original tertiary structure of the allergen, if any, resulting in a reduced ability to bind IgE and therefore to elicit allergic reactions in humans.